Summary Acute respiratory illness (ARI) and acute gastroenteritis (AGE) are leading causes of disease in children in the U.S. and globally. These infections contribute a substantial burden of morbidity, mortality, and direct health care costs, in addition to the indirect costs associated with parental leave from work. Many cases of ARI are caused by viruses, including influenza, respiratory syncytial virus, and others. Similarly, most AGE in the U.S. is associated with viruses, including rotavirus and others. There are few or no effective antivirals for these, and therefore vaccination is the most promising intervention. Licensed vaccines are available for influenza and rotavirus; candidate vaccines for other pathogens are in development. Active, prospective surveillance is necessary to establish ?real-world? vaccine effectiveness (VE). Moreover, population-based surveillance can discover the burden of potentially vaccine- preventable diseases and guide policymakers and industry. The infrastructure provided by the New Vaccine Surveillance Network (NVSN) will facilitate these goals, as well as allowing the description of the clinical features, natural history, and population dynamics of these illnesses. The Children?s Hospital of Pittsburgh (CHP) offers an ideal environment to conduct the proposed population-based research, as CHP is the only major provider of pediatric inpatient and Emergency Department (ED) care in Allegheny County and the region. We propose three Specific Aims. Aim 1: To evaluate the effectiveness and impact(s) of current or upcoming vaccines and other immunoprophylaxis strategies, and inform pediatric vaccine-related policies. Using test-negative case-control methods, we will calculate the annual VE of influenza and rotavirus vaccines against medically attended ARI and AGE. Aim 2: To actively assess the burden of AGE and ARI (including illness with laboratory-confirmed viral etiologies) in the pediatric population. We will perform laboratory confirmation of viral etiologies of ARI and AGE among ill subjects enrolled in the inpatient or ED, and healthy controls enrolled at well-child visits. Aim 3: To establish the natural history of disease for pediatric infectious diseases, transmission dynamics, vaccine impacts for targeted and vulnerable populations, and socioeconomic and microbiological environments potentially relevant to public health interventions. We will capture extensive clinical and demographic data on enrolled subjects and healthy controls. Subjects will be tested for additional ARI- and AGE-associated viruses. The completion of this project will provide new data regarding the VE of licensed vaccines; define the population-based burden of potentially vaccine-preventable diseases; and establish the natural history and disease association of multiple human viruses. These results will guide the development of new vaccines and antivirals, inform public health policies, and enhance the health outcomes of children in the U.S. and globally.